'Elephant Man' Gene Mutation Identified

Action Points

xplain that Proteus syndrome -- the likely affliction of the "Elephant Man" -- is caused by a somatic mutation (an alteration in DNA that occurs after conception, and is passed only to direct descendant cells) in the oncogene AKT1.

Note that the gene affected encodes an enzyme involved in the regulation of cell proliferation and apoptosis.

Proteus syndrome -- the likely affliction of Joseph Merrick, the "Elephant Man" -- is caused by a somatic mutation in the oncogene AKT1, researchers have determined.

Among 29 patients with the Proteus syndrome, 26 had a mutation (c.49G→A, p.Glu17Lys) in the gene that encodes an enzyme involved in the regulation of cell proliferation and apoptosis, according to Leslie G. Biesecker, MD, from the National Institutes of Health in Bethesda, Md., and colleagues.

Writing online in the New England Journal of Medicine, Biesecker's group explained that somatic mutations are alterations in DNA that occur after conception and are passed only to direct descendant cells.

The result is a state known as mosaicism, in which some cells in the body have different genetic makeup than others.

Patients with the Proteus syndrome typically have hyperplasia and overgrowth of numerous organs and tissues that can lead to severe disfigurement and tumors.

More than 20 years ago, it was hypothesized that Proteus syndrome is a mosaic disorder, caused by a mutation that, if found in all cells of the body, would be lethal.

In an editorial accompanying the genome analysis, John M. Opitz, MD, and Lynn B. Jorde, PhD, of the University of Utah in Salt Lake City, noted the "singular success" of Biesecker's group.

"An ingenious hypothesis that certain lethal mutations could survive only in a mosaic state was confirmed previously in patients with McCune-Albright monostotic fibrous dysplasia and now has been confirmed again in the Proteus syndrome," wrote Opitz and Jorde.

The researchers obtained multiple tissue samples from their cohort of patients, both from areas with visible tissue overgrowth as well as from apparently uninvolved sites.

Initially they sequenced the exome, or protein-coding portion of the genome, in 12 patients and relatives, and found the AKT1 variant in seven.

They then assayed 158 samples from the 29 patients.

A total of 97 of the samples had been taken from affected tissues, and in these, 75 had the mutation.

For an additional 20 samples, it was unclear whether the area was affected or not, and in these, 11 had the mutation.

In these 86 positive samples, the quantity of DNA with the mutation ranged from 1% to 47%, the researchers reported.

They then looked at the functional effects of the mutation and determined that it resulted in activation of AKT1 by increasing phosphorylation of the Ser473 and Thr308 residues.

Murine studies have demonstrated that activation of the AKT1 gene has very different effects than its loss of function.

In contrast, those with activated forms of the gene have hyperplasia of the skin and calcification of the cartilage -- a phenotype "strikingly similar to that of the Proteus syndrome," the researchers observed.

Previously, some investigators had suggested that mutations in a different gene, PTEN, were responsible for the Proteus syndrome, while others disagreed.

Biesecker's group pointed out that individuals with PTEN mutations not only have tissue overgrowth, but also features such as lipomas and vascular abnormalities -- the SOLAMEN syndrome.

And they further argued that mutations causing loss of function in the PTEN gene cause activation of AKT1, "which explains why patients with such mutations (those with the SOLAMEN syndrome) and patients with activating mutations in AKT1 (those with the Proteus syndrome) have overlapping but distinct clinical manifestations."

Accordingly, these conditions may be part of a related group of genetic disorders resulting from mutations in genes that encode proteins involved in a signaling pathway known as PI3K-AKT, the researchers suggested.

They noted that, unlike many other disorders, in Proteus syndrome the mutation is found in a single gene.

"We suggest that mosaic disorders are analogous to inherited disorders in that some of them (e.g., the Proteus and McCune-Albright syndromes) are caused by a single variant and others (e.g., many cancers) arise only after the accumulation of many somatic mutations," they wrote.

Editorialists Opitz and Jorde observed that genome sequencing techniques such as were used in this analysis are rapidly being refined, and costs are coming down.

"As our capacity to obtain and analyze DNA sequences continues to increase, solutions to riddles such as the Proteus syndrome may become commonplace. This promises a wellspring of new and exciting discoveries about the basic causes of human disease, and it will aid in accurate diagnoses and effective treatments," Opitz and Jorde predicted.

The study was supported by the National Human Genome Research Institute and the Proteus Syndrome Foundations of the United States and United Kingdom.

Several of the investigators reported being consultants for companies such as Amgen, Medtronic, and K2M Surgical.

Editorialist Jorde has received grants from the National Institutes of Health and the March of Dimes, and is a board member of the Institute for Systems Biology.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.